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103-1 SECTION 12 BONE AND JOINT DISORDERS 103 OSTEOPOROSIS A Bone to Pick with Osteoporosis. . . . . . . . . . . . . . . . Level II Emily C. Papineau, PharmD, BCPS CASE SUMMARY B.F., a 65-year-old woman, presents to a family medicine clinic to discuss results of her dual-energy x-ray absorptiometry (DXA) scan. Her complaints include shortness of breath with exercise and difficulty remembering to take medications. A recent DXA scan reveals osteoporosis. The patient reports a 2″ loss in height, and has evidence of a vertebral compression fracture. The patient requires an osteoporosis therapy regimen that is both efficacious and one to which she can adhere. Estrogen and estrogen plus bazedoxifene therapy should be withheld in this patient not only due to her history of breast cancer but also because estrogen therapy is no longer recommended solely for the prevention of chronic diseases. Feasible treatment alternatives include zoledronic acid, denosumab, ibandronate, risedronate, alendronate, raloxifene, and teriparatide. The patient should also receive 1,200 mg of elemental calcium daily through diet (preferably) and/or supplementation. Vitamin D (cholecalciferol) 800–1000 international units (IU) daily should be considered because many elderly patients are deficient in this vitamin. Nonpharmacologic interventions, such as dietary modification, reduced caffeine, and implementation of a weight-bearing exercise program, play an important role in the management of osteoporosis. QUESTIONS Problem Identification 1.a. Create a list of the patient’s drug therapy problems. • COPD therapy is inadequate. ✓The patient is currently only using ipratropium/albuterol twice daily, instead of four times daily, and reports shortness of breath with prolonged walking. Using the 2016 Global Initiatives for Chronic Obstructive Lung Disease (GOLD) guidelines,1 this patient was classified as being in Patient Group B (GOLD 2, CAT ≥10). The GOLD guidelines indicate that a long-acting bronchodilator be used for patients in this Group B category. Options for therapy include either long-acting β-agonists, such as formoterol, arformoterol, salmeterol, olodaterol, or indacaterol, or long-acting anticholinergics, such as tiotropium, aclidinium bromide, or umeclidinium. Given that the patient has expressed difficulty remembering to take her medications, a once-daily regimen with tiotropium, umeclidinium, indacaterol, or olodaterol (two inhalations once daily) may be preferable and improve adherence. The patient will still need a medication for quick relief of COPD symptoms. If tiotropium or umeclidinium is selected as a maintenance medication, then the short-acting bronchodilator should be switched from ipratropium/albuterol to albuterol alone. This will avoid excessive anticholinergic side effects from using two anticholinergic drugs concurrently. If a long-acting β-agonist is selected, the combination inhaler of ipratropium/albuterol could still be used. Regardless of which long-acting bronchodilator is used, the patient should be instructed on how to properly use the inhaler device to administer the medication.1 Again, recommend tips to help the patient to adhere to her medication regimen. ✓Should this patient’s COPD progress to Group C or D, inhaled corticosteroids would then be indicated. The GOLD guidelines also highlight the current debate as to whether chronic administration of inhaled corticosteroids in COPD may lower bone mineral density (BMD), as some research has shown an increased risk (triamcinolone being most implicated) and some has not. Inhaled corticosteroids are preferred to systemic treatment because they have less osteoporosis risk. For now, this concern can be avoided. In addition to optimizing medication use for COPD, the pharmacist should recommend the patient participate in a pulmonary rehabilitation program and verify that the patient has received the influenza and pneumococcal vaccines, as appropriate.1 • Hypothyroidism is presently controlled. The thyroid stimulating hormone (TSH) level is normal, indicating that the levothyroxine therapy is adequate. The patient’s TSH level should be routinely monitored because overtreatment of hypothyroidism that induces hyperthyroidism can contribute to further loss of BMD.2 • Smoking cessation should be encouraged, as this would help to lower her blood pressure, decrease the rate of decline of her lung function, and decrease the risk of osteoporotic fracture.1–4 Use the “5 As” to guide this process, and discuss the various options to help minimize nicotine withdrawal, including nicotine replacement products, bupropion, and varenicline (http:// www.ahrq.gov/professionals/clinicians-providers/guidelines -recommendations/tobacco/index.html).5 1.b.What information (signs, symptoms, laboratory values, and FRAX score) indicates the presence or severity of the patient’s osteoporosis? What are the patient’s risk factors for osteoporosis? • The DXA scan results reveal that the patient’s BMD is in the osteoporotic range. The World Health Organization (WHO) classifies bone mass based on T-scores which represent the number of standard deviations (SDs) away from the mean BMD for the young normal adult population. Criteria for interpreting the results of a DXA scan are2–4: ✓Normal: T-score within 1.0 SD of young adult mean value ✓Osteopenia: T-score between 1.0 and 2.5 SD below the mean Copyright © 2017 by McGraw-Hill Education. All rights reserved. 103-2 SECTION 12 ✓Osteoporosis: T-score ≥2.5 SD below the young adult mean value • Avoid caffeine intake. Caffeine can increase the excretion of calcium to a small extent and may contribute to low BMD.3 ✓Severe osteoporosis: T-score ≥2.5 SD below the young adult mean value with ≥1 fracture • Reduce the risk of falls by removing obstacles, such as throw rugs and extension cords, and by adding assistive devices, such as handrails to the bathtub and other areas, and obtaining nonskid mats for slippery surfaces. Clarify the quantity and frequency of alcohol consumed, as excessive drinking, particularly >3 drinks/day, could contribute to fall risk. Screening and correcting for vision impairment may also decrease fall risk.4 Bone and Joint Disorders • This patient’s worst T-score is >3 SD from the young adult mean value, and she has one or more fragility fractures (loss of height of >1.5″) and evidence of a vertebral compression fracture.2 Even if the patient had not obtained a DXA scan, the diagnosis of osteoporosis can be made based solely on the presence of a vertebral fracture. A patient with a vertebral fracture is 2–3 times more likely to experience additional fractures.4 • The WHO FRAX score can be calculated to estimate the likelihood of the occurrence of a hip fracture or major osteoporotic fracture (defined as hip, spine, forearm, or shoulder fracture) within the next 10 years in a patient not on osteoporosis treatment. The calculation can be performed (http:// www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) and takes into account many risk factors for osteoporosis. For B.F., her osteoporosis risk factors include her Caucasian ethnicity, age (and postmenopausal status), low body weight evidenced by BMI <21 kg/m2, history of previous fracture, cigarette smoking, history of maternal hip fracture, and femoral neck T-score. B.F. has a 38% chance of experiencing a major osteoporotic fracture and an 11% chance of hip fracture in the next 10 years if her osteoporosis remains untreated. Even if this patient’s DXA scores were not osteoporotic, the National Osteoporosis Foundation (NOF) guidelines and the North American Menopause Society (NAMS) guidelines state that treatment is pharmacoeconomically beneficial if the risk of hip fracture is at least 3% or if the risk of major osteoporotic fracture is at least 20%.2,4 Desired Outcome 2.What are the goals of pharmacotherapy for osteoporosis in this case? • Prevent or decrease the incidence of fractures with a medication regimen that will minimize the potential for nonadherence. • Restore bone mass and/or prevent further bone loss and loss of height. • Prevent falls that can result in debilitating fractures and negatively impact quality of life. • Provide optimal calcium and vitamin D supplementation, in addition to prescription drug therapy. Therapeutic Alternatives 3.a. What nondrug therapies might be useful for this patient’s osteoporosis? • Ensure adequate calcium and vitamin D intake through diet and/or supplementation.2–4 Dairy products are an excellent dietary source of calcium. One cup of milk or yogurt contains approximately 300 mg of elemental calcium. In addition to calcium, milk is often fortified with vitamin D. Cereals are often another source of a vitamin D fortified food. Exposure to sunlight can also cause synthesis of vitamin D in the body. Use of sunlight for this purpose should be balanced against the risk of skin cancer. Use of supplements to achieve adequate calcium and vitamin D intake are discussed below. • Perform regular weight-bearing and muscle-strengthening exercises such as walking, jogging, dancing, and weightlifting.2,4 • Encourage smoking cessation as postmenopausal women who smoke are more likely to experience fractures.2,4 Copyright © 2017 by McGraw-Hill Education. All rights reserved. 3.b.What feasible pharmacotherapeutic alternatives are available for treatment of the osteoporosis? • Adequate calcium ingestion should be recommended for all patients with osteoporosis. Adequate calcium intake is not only essential for achieving peak bone mass and reducing the rate of bone loss, but it is also vital for achieving adequate response to other osteoporosis therapies. Since most individuals over the age of 50 consume 600–700 mg of elemental calcium per day, increasing dietary calcium or taking calcium supplements will be necessary for most women with osteoporosis. ✓Both the NOF and Institute of Medicine recommend 1,200 mg/day of elemental calcium in postmenopausal women.4 Doses >1,500 mg of elemental calcium are not thought to offer any additional benefit but may increase cardiovascular risk.4 Furthermore, doses >2,500 mg can increase the risk of developing kidney stones. ✓Because calcium absorption is rate-limited, calcium supplements should be given in divided doses of approximately 500 mg of elemental calcium.2,3 ✓It is important to note that this patient is on acid suppressive therapy for GERD and that long-term proton pump inhibitor use has been associated with increased risk of hip fractures, especially in women who smoke2,3 (http:// www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm). Although calcium citrate contains less elemental calcium than calcium carbonate, it is not dependent on gastric pH for absorption and, therefore, is a good nondietary choice for older adults who may have achlorhydria and those on acid-suppressive therapy.2,3 It may be taken independent of meals, unlike calcium carbonate which should be taken with meals.2,3 Side effects of constipation and gas are more common with calcium carbonate than with calcium citrate.3 ✓Therapy typically should be lifelong. • Vitamin D enhances calcium absorption in the small intestine, and when combined with calcium, it has been shown to reduce the incidence of nonvertebral fractures in the elderly. It is not necessary for vitamin D and calcium to be administered concurrently for vitamin D to enhance the absorption of calcium because of the long half-life of vitamin D.2 ✓Both the NAMS and NOF osteoporosis guidelines recommend that postmenopausal women take 800–1000 IU of vitamin D daily.2,4 This is because most individuals are thought to be vitamin D deficient, and elderly patients are even more at risk for vitamin D deficiency as a result of inadequate or limited exposure to sunlight.2 This patient is not at high risk for pronounced vitamin D deficiency (such as those with malabsorptive conditions or on phenytoin); however, checking a serum 25(OH)D level is reasonable as many individuals with osteoporosis have vitamin D deficiency, according to the NOF. Vitamin D doses >1000 IU/day may be needed in individuals with deficiency in order to obtain vitamin D levels of approximately 30 ng/mL (75 nmol/L).4 103-3 • Bisphosphonates are considered drugs of choice for the treatment of osteoporosis. They block osteoclast resorptive activity with no effect on osteoblasts. Alendronate, risedronate, and zoledronic acid are the only FDA-approved agents that can decrease the risk of vertebral and nonvertebral fractures, including hip fractures. A case-control study also found that bisphosphonate use reduced the risk of breast cancer in nonobese women.5 While further investigation is needed in this area, this could be a potential added benefit for the patient. ✓Alendronate (Fosamax, Fosamax Plus D, and Binosto) is approved by the FDA for both treatment and prevention of osteoporosis. Alendronate is commonly selected for osteoporosis therapy due to its availability as a lower cost, generic medication. It reduces vertebral fractures and increases BMD in the spine, femoral neck, trochanter, and total body. Specifically, it decreases the risk of fractures in women with established osteoporosis and prevents bone loss in nonosteoporotic women. Alendronate (either alone or in combination with hormone replacement therapy) was shown to be superior to hormone replacement therapy alone for preventing bone loss in elderly women.2 Alendronate has poor oral absorption (0.78%) and must be taken on an empty stomach, which increases side effects. The most common adverse effects are abdominal pain, acid reflux, constipation, diarrhea, musculoskeletal pain, headache, and esophagitis. Alendronate is available in a once-daily dose of 10 mg, which may not be optimal for a patient who expressed difficulty remembering to take medications, especially considering this medication should be taken prior to the first meal of the day. The 70-mg onceweekly dose of alendronate may be easier for the patient to take and come as both a tablet and a 70 mg/75 mL solution. Fosamax Plus D is another once-weekly dosage form that contains either 2,800 or 5,600 IU of cholecalciferol in combination with 70 mg of alendronate. Alendronate can also be obtained as a 70-mg effervescent tablet (Binosto). A potential advantage of Binosto is that it forms a buffered solution and raises the pH of the stomach. Given that B.F. has GERD, this may cause less esophageal irritation if reflux occurs after alendronate ingestion. More studies are needed to determine if this will have a clinical impact on the incidence of esophagitis or dyspepsia in patients using alendronate. ✓Risedronate (Actonel and Atelvia), which is also approved by the FDA for both treatment and prevention of osteoporosis, Copyright © 2017 by McGraw-Hill Education. All rights reserved. Osteoporosis ✓Vitamin D replacement will most likely be given for the rest of the patient’s life. NOF, NAMS, or the American Association of Clinical Endocrinologists (AACE) does not recommend a particular vitamin D supplement over another.2–4 significantly reduces the rate of vertebral and nonvertebral fractures.2,3 Like alendronate, risedronate has poor oral absorption, and regular-release products must be administered on an empty stomach. The side effect profile is similar to that of alendronate and would be expected to cause similar GI side effects. The dose of risedronate (5 mg once daily) is the same for both treatment and prevention of osteoporosis. Alternative regimens include 35-mg once-weekly or 150-mg once-monthly doses. Risedronate also comes as a delayed-release tablet, Atelvia. Unlike other oral bisphosphonate products, Atelvia is to be taken with ≥4 oz. of water immediately after breakfast. As with other oral bisphosphonates, a patient should remain upright for 30 minutes after swallowing Atelvia. ✓Ibandronate (Boniva), a bisphosphonate similar to risedronate and alendronate, is also approved by the FDA for the treatment and prevention of osteoporosis. In patients with established osteoporosis, ibandronate has been shown to increase BMD and reduce the incidence of vertebral fractures. With a T-score below –3, ibandronate has been shown to decrease nonvertebral fractures as well.2 Like alendronate and risedronate, ibandronate’s oral absorption is significantly reduced by the presence of food, and the drug must therefore be administered on an empty stomach, 60 minutes prior to eating or drinking. The oral form also has similar GI side effects as the other oral bisphosphonates. The 150-mg monthly oral dose of ibandronate is available in generic form. Ibandronate is also available as a 3-mg IV injection administered every 3 months by a healthcare professional for the treatment of osteoporosis. This dosage form has been shown to increase BMD to a greater degree than daily oral ibandronate. Because it also requires less frequent dosing, this product may be a treatment option for this patient but may not be as effective as other bisphosphonates in preventing nonvertebral fractures. ✓Zoledronic acid (Reclast) is an intravenously administered bisphosphonate that is FDA-approved for once-yearly treatment of osteoporosis and for treatment once every 2 years for osteopenia. The once-yearly injection for the treatment of postmenopausal osteoporosis was found to decrease the risk of vertebral fractures by 70%, hip fractures by 41%, and other fractures by 25% over a 3-year period.2 It is also the first bisphosphonate to receive FDA-approval to reduce the incidence of new clinical fractures in patients with low-trauma hip fracture. The most common side effects of this treatment include an acute phase reaction of flu-like symptoms such as fever, arthralgia, and myalgia. These side effects occur in 33% of patients with the initial dose, typically resolve within 3 days after drug infusion and can be minimized with the use of acetaminophen prior to and for 3 days following zoledronic acid administration. Subsequent administration of the zoledronic acid tends to cause less flu-like reactions (7% and 3% for the second and third doses, respectively).4 There was concern about zoledronic acid being associated with a statistically significant increase in the incidence of arrhythmia (6.9% zoledronic acid group compared to 5.3% in the placebo group) in the HORIZON trial. Of these arrhythmias, 1.3% of patients given zoledronic acid experienced serious atrial fibrillation, compared with 0.4% of patients given placebo, and most episodes of atrial fibrillation occurred greater than 1 month post-infusion. The FDA reviewed all the data surrounding atrial fibrillation with all bisphosphonates and determined that a causal relationship between the use of these medications, including zoledronic CHAPTER 103 ✓As stated previously, dairy products are the most common dietary source of vitamin D, although adequate amounts of vitamin D can be obtained through other vitamin D-fortified foods as well. Vitamin D-containing supplements have one of two forms of vitamin D, namely, ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3). Cholecalciferol is the form of vitamin D synthesized in the skin from sun exposure and is more potent when administered intermittently than ergocalciferol.3 This form of vitamin D can be found in many common supplements, such as Caltrate +D, Os-Cal 500 +D, and Cal-Citrate with vitamin D. Cholecalciferol is also the form of vitamin D in Fosamax Plus D. Use of vitamin D has also been associated with decreased risk of falls and improvement in muscle strength.2 103-4 SECTION 12 Bone and Joint Disorders acid, and the onset of atrial fibrillation was unclear. The FDA recommends against changing prescribing habits for this class of medications at this time and will continue to monitor postmarketing reports (http://www.fda.gov /Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm). Use of zoledronic acid has also been associated with osteonecrosis of the jaw (ONJ) predominately when used in much higher doses for the treatment of malignancy and in patients who were also receiving chemotherapy and corticosteroids.2,3 This medication would be a great choice for the patient, as it has excellent fractureprevention data, would avoid GI toxicity, and is conveniently administered once yearly, which may help improve patient adherence to the treatment. It is a more costly option than alendronate, but it is often covered by insurance. • Denosumab (Prolia) is an FDA-approved option for the treatment of postmenopausal osteoporosis for those at high risk of fracture, including those with a history of osteoporotic fracture, multiple risk factors for fracture, or those who have failed or are intolerant to other available osteoporosis therapies. It is a human monoclonal antibody which inhibits nuclear factor-kappa ligand (RANKL) activity. RANKL is a protein that essentially promotes osteoclast formation. The FREEDOM trial demonstrated that denosumab, by inhibiting RANKL activity for 3 years, increased BMD in the lumbar spine and hip and decreased the risk of vertebral, hip, and nonvertebral fractures by 68%, 40%, and 20%, respectively.2 One head-to-head trial comparing denosumab to once-weekly 70-mg alendronate, showed that denosumab increased BMD at the total hip to a greater degree after 1 year than did alendronate (3.5% vs 2.6%, respectively; P< 0.0001).6 Denosumab also increased BMD to a greater degree than alendronate at all tested sites and lowered markers of bone turnover more effectively than alendronate. The study was not powered to detect a difference in osteoporotic fractures.7 ✓Denosumab is administered as 60-mg subcutaneously every 6 months by a healthcare professional and is estimated to cost approximately $1,000 per injection but is often covered by insurance (although prior authorization may be required). It has few reported side effects such as back and musculoskeletal pain, hypercholesterolemia, cystitis, and dermatologic conditions like eczema. RANKL is also located on activated T and B lymphocytes and in lymph nodes, so its inhibition may explain the small increased risk of serious infection such as cellulitis and endocarditis. Because it is an antiresorptive medication, reports of ONJ and atypical femur fractures have occurred. A medication guide discussing the risks of therapy is to be distributed to patients. Denosumab is contraindicated in pregnancy and in hypocalcemia. The prescribing information specifies patients should take 1,000 mg of calcium daily and at least 400 IU of vitamin D daily. • Estrogen therapy was once considered the treatment of choice for osteoporosis in postmenopausal women. Estrogen preserves BMD and inhibits bone resorption by decreasing the rate of the bone activation cycle. This results in a lower incidence of hip fractures. Estrogen also provides relief from conditions associated with menopause such as hot flashes. The US Preventive Services Task Force recommends against the routine use of estrogen or estrogen and progestin for the prevention of chronic conditions, such as osteoporosis, due to the potential risks associated with their use.6 This recommendation is due to findings from the Women’s Health Initiative (WHI) study and the Heart and Estrogen/progestin Replacement Study Copyright © 2017 by McGraw-Hill Education. All rights reserved. (HERS) follow-up.6 According to these studies, women receiving hormone therapy were at a higher risk for coronary heart disease, invasive breast cancer, pulmonary embolism, stroke, and biliary tract surgery.8 Since B.F. is already diagnosed with osteoporosis and has a history of breast cancer, this would not be an appropriate therapeutic option for her. • Estrogen agonist/antagonists also known as selective estrogen receptor modulators have estrogen-like effects on cortical bone and antiestrogen-like effects on breast tissue and the endometrium. ✓Raloxifene (Evista) increases BMD but to a lesser extent than estrogen. Raloxifene has only been demonstrated to reduce the incidence of vertebral fractures in postmenopausal women with osteoporosis.2–4 It is indicated for both the prevention and treatment of osteoporosis as well as decreasing the risk of invasive breast cancer in postmenopausal women. Raloxifene also decreases serum total- and LDL-cholesterol concentrations with no effect on HDL or TGs. The 4-year results from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial revealed that raloxifene did not significantly affect overall risk for cardiovascular events in the overall cohort of postmenopausal women, although a reduction in risk was noted in a subset of high-risk women and women with established CHD.2,3 The MORE-CORE trial looked specifically at women with increased cardiovascular risk and found that raloxifene neither increased nor decreased cardiovascular outcomes.2,3 Raloxifene is safe in patients with breast cancer or a history of breast cancer because it is an estrogen antagonist in uterine and breast tissues. Like estrogen, raloxifene use is associated with an increased risk of thromboembolic events, particularly during the first 4 months of treatment. The most common side effects are hot flashes and leg cramps. The usual dose of raloxifene is 60 mg/day. It should be combined with calcium supplementation. This is a therapeutic option for B.F. but may not lower her risk for hip fracture, which is one of her main concerns. • Conjugated estrogens/bazedoxifene (Duavee) is estrogen combined with an estrogen agonist/antagonist and is approved for the treatment of moderate-severe postmenopausal hot flashes and the prevention of osteoporosis. It has been shown to increase BMD in the lumbar spine and total hip. Its side effect profile is like that of estrogen products. Given this patient’s history of breast cancer and that B.F. already has osteoporosis, this product is not ideal for her.4 • Teriparatide (Forteo) is a recombinant human parathyroid hormone with a unique mechanism of action of increasing osteoblast lifespan and function. When administered once daily, it leads to increased bone formation and improved bone quality. Teriparatide is indicated in postmenopausal women who are at high risk for fractures. In postmenopausal women with osteoporosis and a history of prior vertebral fractures, teriparatide significantly improves BMD and reduces the incidence of subsequent fractures.2–4 Teriparatide is administered subcutaneously daily into the abdomen or thigh with a prefilled injectable device; however, it is very expensive relative to other agents used for treating osteoporosis and may require special approval from insurance companies before it is available at a reduced price to the patient. Side effects, although uncommon, include dizziness, leg cramps, and arthralgias. The patient should sit or lie down upon the initial administration of teriparatide to prevent orthostatic hypotension with the first dose. The product also carries a boxed warning due to an increased incidence of the development of osteosarcoma in rats. Teriparatide is contraindicated in patients with a history of Paget’s 103-5 • Combination or Sequential therapy ✓There is some evidence that alendronate or risedronate may increase BMD to a greater extent when used in combination with either estrogen therapy or raloxifene than when used alone. Most research involving the combination of alendronate and teriparatide, demonstrates an antagonistic effect when used concomitantly. Conversely, when alendronate is added after the completion of therapy with teriparatide, alendronate appears to maintain or further increase BMD. This strategy is often employed after teriparatide use. A small study from 2013 revealed that the combination of teriparatide and denosumab increased BMD to a significantly greater extent than either agent alone at the lumbar spine, femoral neck, and total hip.8 Denosumab has also been shown to improve BMD after alendronate therapy is concluded.9 However, due to a lack of data on the long-term safety or effect on fracture rates, the AACE, the NAMS, and the NOF do not recommend routinely using concomitant therapy for the treatment of osteoporosis.2–4 Optimal Plan 4.a. What drug, dosage form, dose, schedule, and duration of therapy are best for treating this patient’s osteoporosis? • A nonoral bisphosphonate (zoledronic acid or ibandronate) is an optimal choice given that this patient has expressed difficulty remembering to take medications. These medications are administered less frequently. Clinics also often have reminder systems to alert patients to when their next dose is due. Zoledronic acid is preferred over ibandronate because of zoledronic acid’s demonstrated efficacy in decreasing nonvertebral and ✓Zoledronic acid given as 5 mg IV every 12 months. ✓Ibandronate given as 3 mg IV every 3 months. ✓The optimal duration of bisphosphonate therapy remains unclear and has recently been debated due to cases of atypical subtrochanteric femur fractures in patients receiving longterm bisphosphonate therapy (typically >5 years).2 Cases of these atypical femur fractures have also been reported in patients not taking bisphosphonate therapy. Information has been added to the medication guide to inform patients of this risk (http://www.fda.gov/Drugs/DrugSafety/ucm229009 .htm). In general, bisphosphonate therapy has not been studied beyond 10 years for alendronate and beyond 3 years with ibandronate or zoledronic acid.2 Despite the long half-life of bisphosphonates, after discontinuation of therapy, eventual decreases in BMD and fracture prevention have been observed.2 Most experts agree that initial use of bisphosphonates for 3–5 years is appropriate.4 The NOF recommends that a risk assessment be performed, including evaluation of BMD measurements, height loss, fracture history during bisphosphonate use, or new conditions or medications that negatively impact BMD. Based upon whether the patient appears to be at modest or high risk for fracture, decisions for continuing therapy should be made. The NOF does not define modest or high risk but states that therapy decisions should be made on an individual basis, as there is no conclusive data to state how long therapy should be continued.4 The Task Force of the American Society for Bone and Mineral Research suggests a more specified approach for postmenopausal women who have been treated with oral bisphosphonates for ≥5 years or IV bisphosphonates for ≥3 years10: ✓For those who have experienced an osteoporotic fracture before or during therapy, consider continuing bisphosphonate therapy or switch to another therapy. Alendronate has been studied for up to 10 years of use and zoledronic acid for up to 6 years of use. ✓ For those who have not experienced an osteoporotic fracture before or during therapy, if the hip BMD T-score is more than 2.5 SD below the mean or the patient is at high risk of fracture (such as age 70–75 years), consider continuing oral bisphosphonate therapy for 10 years or IV bisphosphonate therapy for 6 years or switch to another therapy. ✓ For those who have not experienced an osteoporotic fracture before or during therapy, if the hip BMD T-score is not more than 2.5 SD below the mean or the patient is not at high risk of fracture, consider a drug holiday for 2–3 years. In any of the three scenarios above, the Task Force recommends reassessing the need for therapy or lack thereof every 2–3 years.10 • Denosumab could also be considered a first-line alternative. This patient is at high risk of fracture, given that she has previously had a vertebral fracture. Optimal duration of therapy for denosumab is unknown. If treatment is stopped, loss of BMD occurs quickly.4 ✓Denosumab is dosed as 60 mg subcutaneously every 6 months. Copyright © 2017 by McGraw-Hill Education. All rights reserved. Osteoporosis • Calcitonin-salmon (Miacalcin) inhibits bone resorption by inhibiting osteoclast function and is only indicated for the treatment of osteoporosis in women who are greater than 5 years postmenopause. Calcitonin-salmon significantly increases BMD and reduces vertebral fracture rates in women with established osteoporosis. It has not been shown to decrease nonvertebral or hip fractures.2–4 It also has an analgesic effect and may provide some pain relief in patients with acute vertebral fractures.2 At the time of the writing of this chapter, calcitonin-salmon was available as a nasal spray or subcutaneous injection. Its effect tends to be dose related, and the usual dose is 100 IU SC–200 IU (1 spray intranasally) per day. When using the nasal spray, the patient should alternate nostrils daily. The nasal spray can cause rhinitis, epistaxis, and headache. In 2013, an FDA-advisory committee voted against the continued use of the medication due to a small increase in cancer and in light of its limited efficacy. This cancer risk, recently observed in trials for an oral formulation of the drug, prompted a review of clinical trials with the nasal formulation, where a small risk of cancer was detected. It remains to be seen if the FDA will ultimately permit the product to remain on the market with enhanced warning labels, or if it will be removed from the market. Until then, calcitonin-salmon remains an expensive agent that is less potent than the bisphosphonates, but is an option for patients who cannot tolerate other antiosteoporotic agents or for patients who experience back pain as a result of recent vertebral fractures. vertebral fractures and in preventing recurrent osteoporotic fractures. The convenience of a once-yearly infusion of zoledronic acid compared to a quarterly infusion of ibandronate also makes zoledronic acid a preferred choice for patients as well. If the patient lacks insurance coverage, zoledronic acid and ibandronate are expensive; however, most patients have coverage for this medication through Medicare Part B. CHAPTER 103 disease, unexplained elevations in alkaline phosphatase, open epiphyses, or prior radiation therapy involving the skeleton. Use of teriparatide for more than 2 years is not recommended due to a lack of safety data. Treatment with this agent is often followed by a bisphosphonate to help maintain the BMD increase gained by teriparatide use.4 103-6 SECTION 12 Bone and Joint Disorders • Sufficient calcium intake is essential to increasing bone density. The patient should obtain a total of ~1,200 mg of calcium daily, preferably via her diet. Discussing the calcium content of food may help the patient determine what foods would help her hit this target. The typical diet of a woman >50 years of age contains approximately 600 mg of elemental calcium per day. If she does not reach her calcium goal with diet alone, she needs a calcium supplement to provide the remaining calcium recommended. An example of an appropriate product is Citracal Regular taken as two tablets once daily. Citracal contains calcium citrate, which is better absorbed than calcium carbonate in the elderly and in those on a proton pump inhibitor. The two tablets contain 500 mg of elemental calcium (from calcium citrate) and 400 IU of vitamin D (as cholecalciferol). • Because of her age, the patient should take 800–1000 IU of vitamin D daily. This could be consumed partly from vitamin D fortified foods and in the form of a combination product with calcium, as mentioned above. • Smoking cessation should be encouraged. • Caffeine intake should be minimized. • After receiving medical clearance and minimizing her shortness of breath, the patient should be instructed to participate in an appropriate weight-bearing exercise program for 30 minutes three to five times weekly. She may resume walking around her neighborhood to accomplish this. 4.b. What alternatives would be appropriate if the initial therapy fails or cannot be used? • If the patient has an additional fracture while supposedly on osteoporosis therapy, assess whether the patient was adherent to the regimen. • If the patient cannot tolerate IV bisphosphonate therapy or denosumab therapy, raloxifene 60 mg PO daily could be initiated instead. It may be particularly useful because of its safety in light of the patient’s breast cancer history. Because of its lack of hip fracture data, an antiresorptive medication is initially preferred. • If the patient does not respond to bisphosphonates, denosumab, or raloxifene, or sustains further fractures while taking those medications, teriparatide may be considered. Due to its high cost, teriparatide should be reserved for patients who fail to respond to less expensive therapies. Its daily subcutaneous route of administration is also considered to be less than ideal by most patients, although the Forteo pen device has been redesigned for much easier administration. Giving a bisphosphonate regimen after the completion of teriparatide therapy may help to retain the increases in BMD achieved with teriparatide use. • The combination of ibandronate or zoledronic acid plus raloxifene could be given. Denosumab in combination with teriparatide could also be considered. However, combination therapy has not been well studied and should not be attempted unless maximal therapy with either agent individually is unsatisfactory.2–4 Outcome Evaluation 5.What clinical and laboratory parameters are necessary to evaluate the therapy for achievement of the desired therapeutic outcome and to detect or prevent adverse effects? Efficacy: • The NOF and NAMS recommend repeating the DXA scan in 2 years.3,4 With bisphosphonate therapy, increases in BMD can Copyright © 2017 by McGraw-Hill Education. All rights reserved. typically be observed after 1 year in the spine and after 2 years in the hip.3,4 A DXA scan could therefore be performed after 1 year of therapy; however, Medicare generally covers DXA scans only every 2 years. The optimal therapeutic goal is a significant improvement in lumbar spine and/or femoral neck density, but given her severity of osteoporosis, stabilization of her BMD would also be acceptable. A stable or improved BMD indicates successful treatment, and a reduction in fracture risk is expected.2 In fact, fracture risk reduction is thought to occur even before increases in BMD can be measured.2 • The patient should not experience more fractures or any additional loss of height. Measure the patient’s height at each subsequent visit. If height loss of 2 cm occurs or new back pain develops, another vertebral imaging test is indicated.4 • Biochemical markers of bone turnover are not commonly utilized to evaluate the efficacy of osteoporosis therapy. These markers may play a future role in determining who is at greater fracture risk or when to reinitiate therapy after an osteoporosis drug holiday.4,10 Toxicity monitoring: • For both intravenous ibandronate and zoledronic acid, the manufacturer recommends checking a serum creatinine level prior to each dose. If the creatinine clearance is <30 mL/minute in a patient scheduled to receive ibandronate or <35 mL/minute in a patient scheduled to receive zoledronic acid, then the medications should not be administered due to lack of clinical experience and renal safety data. Furthermore, the prescribing information for zoledronic acid specifies that actual body weight be used in the Cockcroft-Gault equation when calculating creatinine clearance. This patient’s CrCL is approximately 43 mL/minute, so she may use zoledronic acid without being overly concerned that it may cause renal dysfunction. The patient should also have serum calcium levels checked prior to subsequent infusions to rule out hypocalcemia, which is a contraindication with bisphosphonate use. This is also not currently an issue for B.F. since her calcium level is normal. B.F. should be questioned about the occurrence of any side effects such as flulike symptoms, abdominal pain, nausea, vomiting, diarrhea, or bone/muscle pain at each subsequent office visit. Encourage the patient to have good oral hygiene and get any necessary invasive dental procedures done prior to medication administration, because rare reports of ONJ have been described in patients taking bisphosphonates for osteoporosis.2 Increased risks for developing ONJ include poor oral hygiene, invasive dental procedures, and concomitant treatment with chemotherapeutic agents and/or high-dose systemic corticosteroids.2,3 • Rare reports (1 in every 10,000–100,000 patients) of atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients on bisphosphonates for greater than 3–5 years (http://www.fda.gov/Drugs/DrugSafety/ucm229009 .htm).10 It is proposed that the antiresorptive nature of bisphosphonates may lead to impaired bone remodeling and subsequent risk for these uncommon fractures. Patients should be screened for thigh and groin pain, which often preceded these fractures weeks to months before they occurred.4 • As noted above, after 3–5 years of therapy, the need for therapy in B.F. should be reassessed.3,4 • If the patient is on denosumab and her creatinine clearance falls below 30 mL/minute, monitor for hypocalcemia approximately 1 week after administration. Denosumab is generally well tolerated, but musculoskeletal pain, ONJ, atypical fractures, and infections have been infrequently reported with denosumab use. 103-7 6.What information should be provided to the patient to enhance adherence, to ensure successful therapy, and to minimize adverse effects? General information: • Educate the patient on nonpharmacologic interventions to improve bone health such as smoking cessation, avoidance of excessive alcohol and caffeine, and performing regular weightbearing exercise.2 Encourage her to evaluate her home environment and minimize fall risks, as appropriate.4 Zoledronic acid (Reclast) intravenous administration: • Your primary care provider has recommended zoledronic acid to help strengthen your bones and to prevent any bone fractures in your hips or spine. • This injection is given once every year. Be sure to keep all follow-up appointments with your primary care provider. A routine blood test to check your kidneys and calcium level is also done every year prior to your injection while you are getting this medication. Be sure to drink at least two glasses of water a few hours before you receive this medication. • Some patients experience flu-like symptoms, such as fever and muscles aches and pains, for about 3 days after receiving this medication. Patients may experience these symptoms for up to 1 or 2 weeks after getting this medication, although this is uncommon. You can often prevent these symptoms from occurring by taking acetaminophen just before and for 3–4 days after you receive your medication. These side effects often diminish with future doses of the medication. Let your primary care provider know if you experience severe muscle or bone pain or if you experience a dull, achy pain in your thigh or groin, as the latter may indicate the potential for an unusual bone fracture. Here is a medication guide describing more about the medication and the potential for rare but serious side effects. Obtain a dental examination before starting this medication, if you have not had one in the last 6 months. Some patients who have been on this medication for years and have had a tooth removed experience difficulty with their jaw healing. It is best to have major dental work done prior to beginning this medication. • It is important to get enough calcium by eating foods rich in calcium such as yogurt, milk, and cheese, or by taking calcium supplementation if necessary. Take vitamin D supplement containing 800 IU as well. Adequate calcium and vitamin D help this medication to work properly. Ibandronate (Boniva) intravenous administration: • Your primary care provider has prescribed ibandronate (Boniva) to help strengthen your bones and to prevent any further bone fractures in your spine. • This injection is given every 3 months. Be sure to keep all follow-up appointments with your primary care provider. • Some patients experience flu-like symptoms, such as fever and muscles aches and pains, for about 2 days after receiving this medication. You can often prevent this from occurring by taking acetaminophen just before and for a couple of days after getting your medication. These side effects often diminish with future doses of the medication. Let your primary care provider know if you experience severe muscle or bone pain or if you experience a dull, achy pain in your thigh or groin, as the latter may indicate the potential for an unusual bone fracture. Here is a medication guide describing more about the medication and the potential for rare but serious side effects. Obtain a dental exam before starting this medication, if you have not had one in the last 6 months. Some patients who have been on this medication for years and have had a tooth removed experience difficulty with their jaw healing. It is best to have major dental work done prior to beginning this medication. • It is important to get enough calcium by eating foods rich in calcium such as yogurt, milk, and cheese, or by taking calcium supplementation if necessary. Take vitamin D supplement containing 800 IU as well. Adequate calcium and vitamin D help this medication to work properly. Denosumab (Prolia) subcutaneous administration: • Denosumab (Prolia) is a medication prescribed to strengthen your bones and to prevent bone fractures in your hips or spine. • This injection is given once every year. Be sure to keep all follow-up appointments with your primary care provider. • Most people who take denosumab do not notice any side effects, but back pain and infections have been reported. If you notice a dull, achy pain in your thigh or groin, report this to your primary care provider as this may indicate the potential for an unusual bone fracture. • Here is a medication guide describing more about the medication and the potential for rare but serious side effects. Get a dental exam before starting this medication, if you have not had one in the last 6 months. Some patients who have been on this medication for years and have had a tooth removed experience difficulty with their jaw healing. It is best to get major dental work done prior to beginning this medication. • It is important to get enough calcium by eating foods rich in calcium such as yogurt, milk, and cheese, or by taking calcium supplementation if necessary. Take vitamin D supplement containing 800 IU as well. Adequate calcium and vitamin D help this medication to work properly. REFERENCES 1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for diagnosis, management and prevention of chronic obstructive pulmonary disease: updated 2016. Available at: http://goldcopd.org /global-strategy-diagnosis-management-prevention-copd-2016/. Accessed April 20, 2016. 2. The North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17(1):25–54. 3. American Association of Clinical Endocrinologists Osteoporosis Task Force. AACE medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2010;16:1–37. Copyright © 2017 by McGraw-Hill Education. All rights reserved. Osteoporosis • Educate the patient on her risk of osteoporotic fractures if her osteoporosis remains untreated. Discuss the results of her FRAX scores with her. Encourage adherence to the medication regimen as typical adherence to medications for osteoporosis ranges from approximately 25–81%.2,4 Encourage the patient to record when she is due for her next osteoporosis medication on her calendar or in her cell phone. Also, make her aware that while some of these medications have the possibility of rare side effects, the possibility of a disabling hip fracture that could even be life-threatening is much more concerning. This is why treating osteoporosis is so important.10 A routine blood test to check your kidneys and calcium level is also done every 3 months while you are getting this medication. CHAPTER 103 Patient Education 103-8 SECTION 12 Bone and Joint Disorders 4. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporosis Int 2014;25:2359–2381. 5. Newcomb PA, Trentham-Dietz A, Hamptom JM. Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br J Cancer 2010;102:799–802. 6. Moyer VA. Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2013;158:1–34. 7. Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 Trial. J Bone Miner Res 2009;24:153–161. Copyright © 2017 by McGraw-Hill Education. All rights reserved. 8. Tsai JN, Uihlein AV, Kumbhani, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomized trial. Lancet 2013;382:50–56. doi:10.1016/ S0140-6736(13)60856-9. 9. Kendler DL, Roux C, Benhamou CL, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res 2010;25:72–81. 10. Adler RA, Fuleihan GE, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a Task Force of the American Society for Bone and Mineral Research. J bone Miner Res 2016;31:16–35.